POS0230 THE miR-320 FAMILY IS UPREGULATED IN FAST-PROGRESSING RADIOGRAPHIC KNEE OSTEOARTHRITIS: DATA FROM THE OSTEOARTHRITIS INITIATIVE
Authors: S. Ali, O. Espin-Garcia, A. Wong, P. Potla, C. Pastrello, M. Mcintyre, S. Lively, I. Jurisica, R. Gandhi, M. Kapoor
Journal: Annals of the Rheumatic Diseases (2022)

Background There is an outstanding need for prognostic biomarkers to reliably detect fast-progressing knee osteoarthritis (OA) such that preventative interventions can be targeted to this patient population. MicroRNA-sequencing is an unbiased approach for comprehensive profiling of circulating microRNAs in liquid biopsies to discover novel biomarkers of disease. As negative regulators of gene expression, microRNAs hold potential not only as biomarkers, but also as mechanistic drivers of knee OA. Objectives To apply microRNA-sequencing to identify unique circulating microRNAs as potential biomarkers that distinguish fast-progressing radiographic knee OA from both slow- and non-progressing radiographic knee OA. Methods Leveraging the Osteoarthritis Initiative (OAI) longitudinal cohort, we applied our customized microRNA-sequencing pipeline [1] to blood plasma samples collected at both baseline and 4-year follow-up from 106 participants. The disease trajectory for each participant was constructed by plotting their Kellgren-Lawrence (KL) grades over an 8-year follow-up period. Based on these trajectories, we defined fast-progression as an increase from KL 0/1 at baseline to KL 3/4 by 4-year follow-up, slow-progression as an increase from KL 0/1 at baseline to KL 2/3/4 by 8-year follow-up, and non-progression as no increase from KL0/1 at baseline throughout the 8-year follow-up. Following differential expression analysis, we assessed predictive performance and identified putative gene targets for prioritized microRNAs. Results Comparing fast-progressors to both slow-progressors and non-progressors, we identified differentially expressed microRNAs within timepoints (i.e., 48 microRNAs at baseline and 2 microRNAs at 4-year follow-up) and across timepoints. Among these microRNAs were four members of the miR-320 family, with miR-320d showing an increase in fast-progressors at both timepoints, compared to both slow- and non-progressors. The predictive models we constructed included miR-320 members and had good accuracy (area under the receiver operating characteristic curves ranging from 82.6 to 91.9) in distinguishing fast-progressors. Putative gene targets of the miR-320 family included members of the 14-3-3 gene family (Table 1), including YWHAE , whose downregulation in OA cartilage was reported to promote deterioration [2]. Table 1. Predicted gene targets of the miR-320 family include members of the 14-3-3 gene family. 14-3-3 gene family member hsa-miR-320b hsa-miR-320c hsa-miR-320d hsa-miR-320e SFN M M M L YWHAB M M M M YWHAE V V V H YWHAG V V V M YWHAH V V V M YWHAQ V V V M YWHAZ V V V M All mirDIP results with bold text indicating the prediction was among the top 1% for that microRNA/gene target pair. Letters denote the mirDIP score class with V=very high, H=high, M=medium, and L=low. Conclusion This microRNA-sequencing study is the first of its kind, profiling circulating microRNAs at two timepoints in 106 participants with data-driven construction of knee OA trajectories. We identify the miR-320 family of microRNAs to be associated with fast-progressing radiographic knee OA over time. While our data suggest this microRNA family could have applications as prognostic biomarkers for knee OA, and could be regulating gene targets to impact OA severity, validation of these findings in independent longitudinal cohorts is required. References [1]Potla P, Ali SA, Kapoor M. A bioinformatics approach to microRNA-sequencing analysis. Osteoarthritis and Cartilage Open. 2021;3(1):100131. doi: https://doi.org/10.1016/j.ocarto.2020.100131 . [2]Fu W, Hettinghouse A, Chen Y, Hu W, Ding X, Chen M, Ding Y, Mundra J, Song W, Liu R, Yi YS, Attur M, Samuels J, Strauss E, Leucht P, Schwarzkopf R, Liu CJ. 14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis. Ann Rheum Dis. 2021 Dec;80(12):1615-1627. doi: 10.1136/annrheumdis-2021-220000. Disclosure of Interests None declared